This proposal is intended to follow up on the results achieved during the Phase I project The bioavailability of delta-9-THC achieved from suppositories containing the hemisuccinate ester will be further investigated to develop the most effective product for marketing. Different polar esters of delta-9-THC will be prepared and formulated in suppositories using Whitepsol-Hl5 as the base. The ester resulting in the highest bioavailability of THC will be subsequently formulated in different suppository bases and its bioavailability determined in monkeys. This will provide the final formulation to be studied in detail. Stability of the selected ester in bulk as well as in the suppository formulation will be studied. ln addition the kinetics of hydrolysis of the ester in blood will be determined. Dose response (both in bioavailability and physiological effects) will be determined using the suppositories in monkeys. Accumulation of THC will be studied following subchronic administration of the ester in suppositories. In addition, a comparison between delta-9-THC and the selected ester will be made through l.V. injection of the drug in monkeys to determine the relationship between blood levels and biological activities. In mice, the effects of THC and its selected ester and their toxicities will be compared. Finally, a supply of the selected ester will be prepared for future studies during Phase III of the project.